The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice.
The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice.
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DOI：
10.1002/hep.29076
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Zhou H
中科院分区：
文献类型：
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作者：
Wang Y;Aoki H;Yang J;Peng K;Liu R;Li X;Qiang X;Sun L;Gurley EC;Lai G;Zhang L;Liang G;Nagahashi M;Takabe K;Pandak WM;Hylemon PB;Zhou H
胆管阻塞是胆管细胞增殖的强烈刺激因素，尤其对于大胆管细胞而言。我们先前的研究报道，结合胆汁酸（CBAs）通过肝细胞和胆管癌细胞中的1 - 磷酸鞘氨醇受体2（S1PR2）激活AKT和ERK1/2信号通路。也有报道称牛磺胆酸（TCA）促进大胆管细胞增殖，并保护胆管细胞免受胆管结扎（BDL）诱导的凋亡。然而，S1PR2在胆汁酸介导的胆管细胞增殖和胆汁淤积性肝损伤中的作用尚未阐明。在此我们报道S1PR2是胆管细胞中表达的主要S1PR。在胆管细胞中，JTE - 013（一种S1PR2的特异性拮抗剂）抑制TCA和S1P诱导的ERK1/2和AKT的激活。此外，在小鼠胆管细胞中，JTE - 013、S1PR2的特异性shRNA以及ERK1/2和AKT的化学抑制剂抑制TCA和S1P诱导的细胞增殖和迁移。在胆管结扎小鼠中，全肝和胆管细胞中S1PR2的表达上调。S1PR2缺失显著减少胆管结扎诱导的胆管细胞增殖和胆汁淤积性损伤，这表现为S1PR2 - / - 小鼠的炎症和肝纤维化显著减轻。用JTE - 013治疗胆管结扎小鼠显著降低血清中总胆汁酸水平和胆汁淤积性肝损伤。这项研究表明，结合胆汁酸诱导的S1PR2介导的信号通路的激活在梗阻性胆汁淤积中起关键作用，并可能代表胆汁淤积性肝病的一个新的治疗靶点。
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the AKT and ERK1/2 signaling pathways via the sphingosine 1-phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)-induced apoptosis. However, the role of S1PR2 in bile acid-mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA- and S1P-induced activation of ERK1/2 and AKT were inhibited by JTE-013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA- and S1P-induced cell proliferation and migration were inhibited by JTE-013 and a specific shRNA of S1PR2 as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, the expression of S1PR2 was upregulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL-induced cholangiocyte proliferation and cholestatic injury as indicated by significant reduction of inflammation and liver fibrosis in S1PR2−/− mice. Treatment of BDL mice with JTE-013 significantly reduced total bile acid levels in the serum and cholestatic liver injury. This study suggests that the CBA-induced activation of S1PR2-mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases.